Compounds for the treatment of cancer and inflammatory diseases

ABSTRACT

The present invention relates to novel compounds and pharmaceutical compositions thereof which may be useful in the treatment and/or prevention of various conditions. The present invention also provides methods of preparing such compounds and compositions, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/034,129, filed May 3, 2016, which is a 371 National Stage ofInternational Application No. PCT/US2014/071846, filed Dec. 22, 2014,which claims priority to U.S. Provisional Patent Application No.61/922,227, filed Dec. 31, 2013, each of which is hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds and pharmaceuticalcompositions thereof which may be useful in the treatment and/orprevention of various conditions. The present invention also providesmethods of preparing such compounds and compositions, and methods ofusing the same.

BACKGROUND OF THE INVENTION

A need exists for new drug therapies having greater receptor selectivityfor the treatment of subjects suffering from or susceptible to thediseases, disorders or conditions described herein. In addition, a needstill exists for new drugs having one or more improved properties eitheralone or when combined with other agents (such as safety profile,efficacy, or physical properties) relative to those therapies currentlyavailable.

SUMMARY OF THE INVENTION

In various embodiments, provided herein are compounds of Formula I, orpharmaceutically acceptable salt, solvate, analog, prodrug, isomer ortautomer thereof:

wherein:

-   X₁ and X₂ are independently selected from O, NR₁, or CR₁R₂; wherein,    R₁ and R₂ are independently selected from H, halogen, substituted or    unsubstituted C₁-C₈ alkyl and heteroalkyl, substituted or    unsubstituted C₃-C₆ cycloalkyl and heterocycloalkyl; and R₁ and R₂    can be joined to form a ring;-   Y₁, Y₂, and Y₃ are independently selected from N, CH, or CR₁;-   R₃ is Ar or

-    wherein, L_(a) is CH₂, O, NH, or S; Ar is a substituted or    unsubstituted aryl, or a substituted or unsubstituted heteroaryl;-   R₄ and R₅ are independently selected from H, substituted or    unsubstituted C₁-C₈ alkyl;-   G is

-    where    -   (a) R₇ and R₈ are H; R₆ is H, substituted or unsubstituted C₁-C₄        alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈        alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈        alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₈ alkyl C₃-C₆        cycloalkyl, substituted or unsubstituted aryl, substituted or        unsubstituted C₂-C₈ heterocycloalkyl, substituted or        unsubstituted heteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl        (heteroaryl), C₁-C₈ alkylethers, C₁-C₈ alkylamides, or C₁-C₄        alkyl (C₂-C₈ heterocycloalkyl);    -   (b) R₆ and R₈ are H; R₇ is H, substituted or unsubstituted C₁-C₄        alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈        alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈        alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₈ alkyl C₃-C₆        cycloalkyl, substituted or unsubstituted aryl, substituted or        unsubstituted C₂-C₈ heterocycloalkyl, substituted or        unsubstituted heteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl        (heteroaryl), C₁-C₈ alkylethers, C₁-C₈ alkylamides, or C₁-C₄        alkyl (C₂-C₈ heterocycloalkyl); or    -   (c) R₇ and R₈ taken together form a bond; R₆ is substituted or        unsubstituted C₁-C₄ alkyl, substituted or unsubstituted C₁-C₄        heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈        hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted        or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₈ alkyl C₃-C₆ cycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted C₂-C₈ heterocycloalkyl, substituted        or unsubstituted heteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl        (heteroaryl), C₁-C₈ alkylethers, C₁-C₈ alkylamides, or C₁-C₄        alkyl (C₂-C₈ heterocycloalkyl).

In various embodiments, provided herein are compounds of Formula II, orpharmaceutically acceptable salt, solvate, analog, prodrug, isomer ortautomer thereof:

wherein:

-   X₁ and X₂ are independently selected from O, NR₁, or CR₁R₂; wherein,    R₁ and R₂ are independently selected from H, halogen, substituted or    unsubstituted C₁-C₈ alkyl and heteroalkyl, substituted or    unsubstituted C₃-C₆ cycloalkyl and heterocycloalkyl; and R₁ and R₂    can be joined to form a ring;-   Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, and Y₇ are independently selected from N,    CH, or CR₁;-   R₄ and R₅ are independently selected from H, substituted or    unsubstituted C₁-C₈ alkyl;-   G is

-    where    -   (a) R₇ and R₈ are H; R₆ is H, substituted or unsubstituted C₁-C₄        alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈        alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈        alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₈ alkyl C₃-C₆        cycloalkyl, substituted or unsubstituted aryl, substituted or        unsubstituted C₂-C₈ heterocycloalkyl, substituted or        unsubstituted heteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl        (heteroaryl), C₁-C₈ alkylethers, C₁-C₈ alkylamides, or C₁-C₄        alkyl (C₂-C₈ heterocycloalkyl);    -   (b) R₆ and R₈ are H; R₇ is H, substituted or unsubstituted C₁-C₄        alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈        alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈        alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₈ alkyl C₃-C₆        cycloalkyl, substituted or unsubstituted aryl, substituted or        unsubstituted C₂-C₈ heterocycloalkyl, substituted or        unsubstituted heteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl        (heteroaryl), C₁-C₈ alkylethers, C₁-C₈ alkylamides, or C₁-C₄        alkyl (C₂-C₈ heterocycloalkyl); or    -   (c) R₇ and R₈ taken together form a bond; R₆ is substituted or        unsubstituted C₁-C₄ alkyl, substituted or unsubstituted C₁-C₄        heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈        hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted        or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₈ alkyl C₃-C₆ cycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted C₂-C₈ heterocycloalkyl, substituted        or unsubstituted heteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl        (heteroaryl), C₁-C₈ alkylethers, C₁-C₈ alkylamides, or C₁-C₄        alkyl (C₂-C₈ heterocycloalkyl).

Also provided herein are compounds of Formula IIA, or pharmaceuticallyacceptable salt, solvate, analog, prodrug, isomer or tautomer thereof:

wherein Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, and Y₇ are independently selected fromN, CH, or CR₁;

-   R₄ and R₅ are independently selected from H, substituted or    unsubstituted C₁-C₈ alkyl;-   G is

-    where

R₇ and R₈ are H; R₆ is H, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl,C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substitutedor unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈alkyl C₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl (heteroaryl), C₁-C₈alkylethers, C₁-C₈ alkylamides, or C₁-C₄ alkyl (C₂-C₈ heterocycloalkyl);

R₆ and R₈ are H; R₇ is H, substituted or unsubstituted C₁-C₄ alkyl,substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl,C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substitutedor unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈alkyl C₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₄ alkyl (aryl), C₁-C₄ alkyl (heteroaryl), C₁-C₈alkylethers, C₁-C₈ alkylamides, or C₁-C₄ alkyl (C₂-C₈ heterocycloalkyl);or

R₇ and R₈ taken together form a bond; R₆ is substituted or unsubstitutedC₁-C₄ alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl,substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₄ alkyl(aryl), C₁-C₄ alkyl (heteroaryl), C₁-C₈ alkylethers, C₁-C₈ alkylamides,or C₁-C₄ alkyl (C₂-C₈ heterocycloalkyl).

In further or alternative embodiments, the compound of Formula (I andII) has the following structure of Formula (III-VIII)

In further or alternative embodiments, R₄ is either H or methyl; and Gis selected from among

In some specific embodiments, the compounds have the followingstructures, or pharmaceutically acceptable salt, solvate, analog,prodrug, isomer or tautomer thereof:

Also provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula I, Formula II,Formula III, Formula IV, Formula V, Formula VI, Formula VII, FormulaVIII or a pharmaceutically acceptable salt, solvate, analog, prodrug,isomer or tautomer thereof, and at least one pharmaceutically acceptableinactive ingredient selected from pharmaceutically acceptable diluents,pharmaceutically acceptable excipients, and pharmaceutically acceptablecarriers.

The details of additional embodiments are set forth in the accompanyingdrawings and the description below. Other features, objects, andadvantages of the embodiments will be apparent from the drawings anddetailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

The above description of the disclosed embodiments is provided to enableany person skilled in the art to make or use the invention. Variousmodifications to these embodiments will be readily apparent to thoseskilled in the art, and the generic principles described herein can beapplied to other embodiments without departing from the spirit or scopeof the invention. Thus, it is to be understood that the description anddrawings presented herein represent a presently preferred embodiment ofthe invention and are therefore representative of the subject matterwhich is broadly contemplated by the present invention. It is furtherunderstood that the scope of the present invention fully encompassesother embodiments that may become obvious to those skilled in the artand that the scope of the present invention is accordingly not limited.

The compounds of the invention can be prepared by a variety ofprocedures, some of which are described below. All substituents, unlessotherwise indicated, are as previously defined. The products of eachstep can be recovered by conventional methods including extraction,evaporation, precipitation, chromatography, filtration, trituration,crystallization, and the like. The procedures may require protection ofcertain groups, for example hydroxy, amino, or carboxy groups tominimize unwanted reactions. The selection, use, and removal ofprotecting groups are well known and appreciated as standard practice,for example T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Chemistry (John Wiley and Sons, 1991).

Certain Exemplary Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereis a plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless otherwise stated.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, but not limited to, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4.sup.TH ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the skill of the art are employed. Unless specific definitionsare provided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques can be used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. Reactions andpurification techniques can be performed e.g., using kits ofmanufacturer's specifications or as commonly accomplished in the art oras described herein. The foregoing techniques and procedures can begenerally performed of conventional methods well known in the art and asdescribed in various general and more specific references that are citedand discussed throughout the present specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods and compositions described herein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety may also be an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group consistingof at least two carbon atoms and at least one carbon-carbon double bond,and an “alkyne” moiety refers to a group consisting of at least twocarbon atoms and at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, may be branched, straightchain, or cyclic. Depending on the structure, an alkyl group can be amonoradical or a diradical (i.e., an alkylene group).

The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., upto and including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated).

The alkyl group could also be a “lower alkyl” having 1 to 6 carbonatoms.

The alkyl group of the compounds described herein may be designated as“C₁-C₄ alkyl” or similar designations. By way of example only, “C₁-C₄alkyl” indicates that there are one to four carbon atoms in the alkylchain, i.e., the alkyl chain is selected from the group consisting ofmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

An “alkoxy” group refers to a (alkyl)O-group, where alkyl is as definedherein. A “lower alkoxy” has 1 to 6 carbon atoms.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═CR₂, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃ and —C(CH₃)═CHCH₃.The alkenyl moiety may be branched, straight chain, or cyclic (in whichcase, it would also be known as a “cycloalkenyl” group). Depending onthe structure, an alkenyl group can be a monoradical or a diradical(i.e., an alkenylene group). A “lower alkenyl” has 2 to 6 carbon atomsin the chain.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y), group, wherealkyl is as defined herein and x and y are selected from the group x=1,y=1 and x=2, y=0. When x=2, the alkyl groups taken together with thenitrogen atom to which they are attached can optionally form aheterocyclic ring system.

An “amide” is a chemical moiety with formula —C(═O)NHR or —NHC(═O)R,where R is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic(bonded through a ring carbon). An amide may be an amino acid or apeptide molecule attached to a compound described herein, such as, forexample, a compound of Formula (I), thereby forming a prodrug. Any amineor carboxyl side chain on the compounds described herein can beamidified. The procedures and specific groups to make such amides areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein by reference in its entirety.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any hydroxy, or carboxyl side chain on thecompounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

The term “fused” refers to structures in which two or more rings shareone or more bonds.

The term “carbocyclic” or “carbocycle” refers to a ring wherein each ofthe atoms forming the ring is a carbon atom. Carbocycle includes aryland cycloalkyl. The term thus distinguishes carbocycle from heterocycle(“heterocyclic”) in which the ring backbone contains at least one atomwhich is different from carbon (i.e a heteroatom). Heterocycle includesheteroaryl and heterocycloalkyl. Carbocycles and heterocycles can beoptionally substituted.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl,fluorenyl, and indenyl. Depending on the structure, an aryl group can bea monoradical or a diradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyl groups include groups having from 3 to 10 ringatoms. Depending on the structure, a cycloalkyl group can be amonoradical or a diradical (e.g., an cycloalkylene group). Monocycliccycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A “lowercycloalkyl” has 3 to 8 ring carbon atoms.

A “cycloalkylalkyl” refers to an alkyl, as defined herein, substitutedwith a cycloalkyl, as defined herein. Cycloalkylalkyls include, but arenot limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, and cyclooctylmethyl.

A “cycloalkoxy” refers to —O-(cycloalkyl), where cycloalkyl is asdefined herein. A lower cycloalkoxy has 3 to 8 carbons.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. The polycyclicheteroaryl group may be fused or non-fused. Depending on the structure,a heteroaryl group can be a monoradical or a diradical (i.e., aheteroarylene group).

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Non-aromatic heterocyclic groupsinclude groups having only 3 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems.

An example of a 3-membered heterocyclic group is aziridinyl. An exampleof a 4-membered heterocyclic group is azetidinyl (derived fromazetidine). An example of a 5-membered heterocyclic group is thiazolyl.An example of a 6-membered heterocyclic group is pyridyl, and an exampleof a 10-membered heterocyclic group is quinolinyl.

Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3H-indolyland quinolizinyl.

Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups may be C-attached or N-attachedwhere such is possible. For instance, a group derived from pyrrole maybe pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, agroup derived from imidazole may be imidazol-1-yl or imidazol-3-yl (bothN-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (allC-attached). The heterocyclic groups include benzo-fused ring systemsand ring systems substituted with one or two oxo (═O) moieties such aspyrrolidin-2-one. Depending on the structure, a heterocycle group can bea monoradical or a diradical (i.e., a heterocyclene group).

A “heteroalicyclic” or “heterocycloalkyl” group refers to a cycloalkylgroup that includes at least one ring atom that is not a carbon, i.e. atleast one ring atom is a heteroatom selected from nitrogen, oxygen andsulfur. The heterocycloalkyl radicals may be fused with an aryl orheteroaryl. The term heteroalicyclic also includes all ring forms of thecarbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Heterocycloalkyls have from 2 to10 carbons in the ring. A “lower heterocycloalkyl” has 2 to 8 ringcarbon atoms. It is understood that when referring to the number ofcarbon atoms in a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same at the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e skeletal atomsof the heterocycloalkyl ring).

The terms “halo”, “halide”, and “halogen” mean fluoro, chloro, bromo andiodo.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures that aresubstituted with one or more halogens.

The halogens may the same or they may be different. A “lower haloalkyl”has 1 to 6 carbon atoms in the chain. A “lower haloalkenyl” has 2 to 6carbon atoms in the chain. A “lower haloalkynyl” has 2 to 6 carbon atomsin the chain. A “lower haloalkoxy” has 1 to 6 carbon atoms in the chain.

The terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl andhaloalkoxy groups, respectively, in which the halo is fluorine. A “lowerfluoroalkyl” and a “lower fluoroalkoxy” have 1 to 6 carbon atoms in thechain.

The terms “heteroalkyl” “heteroalkenyl” and “heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl radicals and whichhave one or more skeletal chain atoms selected from an atom other thancarbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, orcombinations thereof. The heteroatom(s) may be placed at any interiorposition of the heteroalkyl group. Examples include, but are not limitedto, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to twoheteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. A “lower heteroalkyl” has 1 to 6 carbon atoms inthe chain. A “lower heteroalkenyl” has 2 to 6 carbon atoms in the chain.A “lower heteroalkynyl” has 2 to 6 carbon atoms in the chain.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “cyano” group refers to a —CN group.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

“Acyl” refers to a RC(═O)— group.

“Acyloxy” refers to a RC(═O)O— group.

“Sulfanyl” refers to a —S— moiety.

“Sulfinyl” or “sulfoxide” refers to a —S(═O)— moiety.

“Sulfonyl” refers to a —S(═O)₂— moiety.

A “mercaptyl” group or “thioalkoxy” or “alkylthio” refers to a (alkyl)S—group.

A “thiocyanato” group refers to a —CNS group.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon).

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from C₁-C₆alkyl,C₃-C₈cycloalkyl, aryl, heteroaryl, C₂-C₆heteroalicyclic, hydroxy,C₁-C₆alkoxy, aryloxy, C₁-C₆alkylthio, arylthio, C₁-C₆alkylsulfoxide,arylsulfoxide, C₁-C₆alkylsulfone, arylsulfone, cyano, halo, C₂-C₈acyl,C₂-C₈acyloxy, nitro, C₁-C₆haloalkyl, C₁-C₆fluoroalkyl, and amino,including C₁-C₆alkylamino, and the protected derivatives thereof.

By way of example only, an optional substituents may be L^(s)R^(s),wherein each L^(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(═O)—, —C(═O)NH—, S(═O)₂NH—,—NHS(═O)₂—, —OC(═O)NH—, —NHC(═O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-;and each R^(s) is independently selected from H, (C₁-C₄alkyl),(C₃-C₈cycloalkyl), heteroaryl, aryl, and C₁-C₆heteroalkyl. Optionallysubstituted non-aromatic groups may be substituted with one or more oxo(═O). The protecting groups that may form the protective derivatives ofthe above substituents are known to those of skill in the art.

The compounds presented herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art such as, for example,the separation of individual stereoisomers by chiral chromatographiccolumns or by stereoselective synthesis.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds having the structure ofany of Formula I, Formula II, Formula III, Formula IV, Formula V,Formula VI, Formula VII, Formula VIII, as well as active metabolites ofthese compounds having the same type of activity. In some situations,compounds may exist as tautomers. All tautomers are included within thescope of the compounds presented herein.

In addition, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth,inflammation or inflammation-related processes, and amelioration of oneor more symptoms associated with a disease or condition.

The term “cancer,” as used herein refers to an abnormal growth of cells,which tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological tumors (such as the leukemias). See, Ding X Z et al.,Anticancer Drugs. 2005 June; 16(5):467-73. Review; Chen X et al., ClinCancer Res. 2004 Oct. 1; 10(19):6703-9, each of which are incorporatedby reference herein in their entirety.

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms.

An appropriate “effective” amount in any individual case may bedetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acidmolecule to aromatic alcohols, aliphatic alcohols, carboxylic acids,amines and free sulfhydryl groups. Further information on metabolism maybe obtained from The Pharmacological Basis of Therapeutics, 9th Edition,McGraw-Hill (1996). Metabolites of the compounds disclosed herein can beidentified either by administration of compounds to a host and analysisof tissue samples from the host, or by incubation of compounds withhepatic cells in vitro and analysis of the resulting compounds. Bothmethods are well known in the art.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like.

In one embodiment of the methods and compositions provided herein, themammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Exemplary Pharmaceutical Compositions/Formulations

For convenience, the pharmaceutical compositions and formulationsdescribed in this section and other parts herein use a single formula,such as “Formula I,” by way of example. In addition, the pharmaceuticalcompositions and formulations described herein apply equally well to allformulae presented herein that fall within the scope of Formula (I). Forexample, the pharmaceutical compositions and formulations describedherein can be applied to compounds having the structure of any ofFormula I, Formula II, Formula III, Formula IV, Formula V, Formula VI,Formula VII, Formula VIII, as well as to all of the specific compoundsthat fall within the scope of these generic formulae.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. A summary of pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference in their entirety.

Provided herein are pharmaceutical compositions that include a compounddescribed herein and a pharmaceutically acceptable diluent(s),excipient(s), and/or carrier(s). In addition, the compounds describedherein can be administered as pharmaceutical compositions in whichcompounds described herein are mixed with other active ingredients, asin combination therapy.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism. In practicingthe methods of treatment or use provided herein, therapeuticallyeffective amounts of compounds described herein are administered in apharmaceutical composition to a mammal having a disease or condition tobe treated. Preferably, the mammal is a human. A therapeuticallyeffective amount can vary widely depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The compounds can be used singly or incombination with one or more therapeutic agents as components ofmixtures.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

For oral administration, compounds described herein can be formulatedreadily by combining the active compounds with pharmaceuticallyacceptable carriers or excipients well known in the art. Such carriersenable the compounds described herein to be formulated as tablets,powders, pills, dragees, capsules, liquids, gels, syrups, elixirs,slurries, suspensions and the like, for oral ingestion by a patient tobe treated.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, but are notlimited to, fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as: for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, or gels formulated in a conventional manner.Parental injections may involve bolus injection or continuous infusion.Formulations for injection may be presented in unit dosage form, e.g.,in ampoules or in multi-dose containers, with an added preservative. Thepharmaceutical composition of the compounds described herein may be in aform suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compound(s) in water-solubleform. Additionally, suspensions of the active compounds may be preparedas appropriate oily injection suspensions. Suitable lipophilic solventsor vehicles include fatty oils such as sesame oil, or synthetic fattyacid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds described herein can be administered topically and can beformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compounds can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel.

Conversely, absorption enhancers can be used to increase absorption. Anabsorption enhancer or carrier can include absorbable pharmaceuticallyacceptable solvents to assist passage through the skin. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin.

For administration by inhalation, the compounds described herein may bein a form as an aerosol, a mist, or a powder. Pharmaceuticalcompositions of compounds described herein are conveniently delivered inthe form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Pharmaceutical compositions may be formulated in conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. Pharmaceutical compositions thatinclude a compound described herein may be manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical compositions will include at least onepharmaceutically acceptable carrier, diluent and/or excipient and acompound described herein as an active ingredient in free-acid orfree-base form, or in a pharmaceutically acceptable salt form. Inaddition, the methods and pharmaceutical compositions described hereininclude the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein. In someembodiments, cyclic compounds described herein may exist in equilibriumwith open chain forms. Both forms, cyclic and open form, are included.Additionally, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein. Inaddition, the pharmaceutical compositions may include other medicinal orpharmaceutical agents, carriers, adjuvants, such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure, and/or buffers. In addition, thepharmaceutical compositions can also contain other therapeuticallyvaluable substances.

Methods for the preparation of compositions that include the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions that include a compound describedherein, or a solution containing liposomes, micelles, or nanoparticlesthat include a compound as disclosed herein. Semi-solid compositionsinclude, but are not limited to, gels, suspensions and creams. Thecompositions may be in liquid solutions or suspensions, solid formssuitable for solution or suspension in a liquid prior to use, or asemulsions. These compositions may also contain minor amounts ofnontoxic, auxiliary substances, such as wetting or emulsifying agents,pH buffering agents, and so forth.

A composition that includes a compound described herein canillustratively take the form of a liquid where the agents are present insolution, in suspension, or both. Typically when the composition isadministered as a solution or suspension, a first portion of thecompound is present in solution and a second portion of the compound ispresent in particulate form, in suspension in a liquid matrix. In someembodiments, a liquid composition may include a gel formulation. Inother embodiments, the liquid composition is aqueous.

Aqueous suspensions can also contain one or more polymers as suspendingagents.

Useful polymers include water-soluble polymers such as cellulosicpolymers, e.g., hydroxypropyl methylcellulose, and water-insolublepolymers such as cross-linked carboxyl-containing polymers. Usefulcompositions can also include a mucoadhesive polymer, selected from, forexample, carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate, and dextran.

Compositions may also include solubilizing agents to aid in thesolubility of a compound described herein. The term “solubilizing agent”generally includes agents that result in formation of a micellarsolution or a true solution of the agent. Certain acceptable nonionicsurfactants, for example polysorbate 80, can be useful as solubilizingagents, as can ophthalmically acceptable glycols, polyglycols, e.g.,polyethylene glycol 400, and glycol ethers.

Compositions may also include one or more pH adjusting agents orbuffering agents, including acids such as acetic acid, boric acid,citric acid, lactic acid, phosphoric acid and hydrochloric acid; basessuch as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodiumphosphate, sodium borate, sodium citrate, sodium acetate, sodium lactateand tris-hydroxymethylaminomethane; and buffers such ascitrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids,bases and buffers are included in an amount required to maintain pH ofthe composition in an acceptable range.

Compositions may also include one or more salts in an amount required tobring osmolality of the composition into an acceptable range. Such saltsinclude those having sodium, potassium or ammonium cations and chloride,citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfateor bisulfite anions; suitable salts include sodium chloride, potassiumchloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

Other compositions may also include one or more preservatives to inhibitmicrobial activity. Suitable preservatives include mercury-containingsubstances such as merfen and thiomersal; stabilized chlorine dioxide;and quaternary ammonium compounds such as benzalkonium chloride,cetyltrimethylammonium bromide and cetylpyridinium chloride.

Still other compositions may include one or more surfactants to enhancephysical stability or for other purposes. Suitable nonionic surfactantsinclude polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylenealkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

Still other compositions may include one or more antioxidants to enhancechemical stability where required. Suitable antioxidants include, by wayof example only, ascorbic acid and sodium metabisulfite.

Aqueous suspension compositions can be packaged in single-dosenon-reclosable containers. Alternatively, multiple-dose reclosablecontainers can be used, in which case it is typical to include apreservative in the composition.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as N-methylpyrrolidone also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds over the course of 4-24 hours. Depending on thechemical nature and the biological stability of the therapeutic reagent,additional strategies for protein stabilization may be employed.

All of the formulations described herein may benefit from antioxidants,metal chelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Exemplary Methods of Dosing and Treatment Regimens

For convenience, the methods of dosing and treatment regimens describedin this section and other parts herein use a single formula by way ofexample. In addition, the methods of dosing and treatment regimensdescribed herein apply equally well to all formulae presented hereinthat fall within the scope of Formula (I). For example, the methods ofdosing and treatment regimens described herein can be applied tocompounds having the structure of any of Formula I, Formula II, FormulaIII, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, aswell as to all of the specific compounds that fall within the scope ofthese generic formulae.

The compounds described herein can be used in the preparation ofmedicaments for the treatment or prevention of a specific disease orcondition. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein or a pharmaceutically acceptablesalt, pharmaceutically acceptable N-oxide, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder, or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds described hereinmay be administered chronically, that is, for an extended period oftime, including throughout the duration of the patient's life in orderto ameliorate or otherwise control or limit the symptoms of thepatient's disease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds described herein may begiven continuously; alternatively, the dose of the compounds describedherein being administered may be temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Thelength of the drug holiday can vary between 2 days and 1 year, includingby way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days,10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days,100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days,300 days, 320 days, 350 days, and 365 days. The dose reduction during adrug holiday may be from 10%-100%, including by way of example only 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved state of the disease,disorder or condition is maintained. Patients can, however, requireintermittent treatment on a long-term basis upon any recurrence ofsymptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., age, weight, gender,etc.) of the subject or host in need of treatment, but can neverthelessbe routinely determined in a manner known in the art according to theparticular circumstances surrounding the case, including, e.g., thespecific agent being administered, the route of administration, thecondition being treated, and the subject or host being treated. Ingeneral, however, doses employed for adult human treatment willtypically be in the range of 0.02-5000 mg per day, in some embodiments1-1500 mg per day. The desired dose may conveniently be presented in asingle dose or as divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described herein arefrom about 0.01 to 2.5 mg/kg per body weight. An indicated daily dosagein the larger mammal, including, but not limited to, humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered individed doses, including, but not limited to, up to four times a day orin extended release form. Suitable unit dosage forms for oraladministration include from about 1 mg to about 50 mg active ingredient.The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

In effecting treatment of a patient in need of such treatment, acompound of the invention can be administered in any form and routewhich makes the compound bioavailable. The compounds of the inventioncan be administered by a variety of routes, including oral andparenteral routes, more particularly by inhalation, subcutaneously,intramuscularly, intravenously, transdermally, intranasally, rectally,vaginally, occularly, topically, sublingually, and buccally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,intraadiposally, intrathecally and via local delivery for example bycatheter or stent.

One skilled in the art can readily select the proper form and route ofadministration depending upon the particular characteristics of thecompound selected, the disorder or condition to be treated, the stage ofthe disorder or condition, and other relevant circumstances. Thepharmaceutical compositions of the invention may be administered to thepatient, for example, in the form of tablets, capsules, cachets, papers,lozenges, wafers, elixirs, ointments, transdermal patches, aerosols,inhalants, suppositories, solutions, and suspensions.

The pharmaceutical compositions of the present invention are prepared ina manner well known in the pharmaceutical art and include at least oneof the compounds of the invention as the active ingredient. The amountof a compound of the present invention may be varied depending upon itsparticular form and may conveniently be between 1% to about 70% of theweight of the unit dosage form. The term “pharmaceutically acceptableexcipient” refers to those typically used in preparing pharmaceuticalcompositions and should be pharmaceutically pure and non-toxic in theamounts used. They generally are a solid, semi-solid, or liquid materialwhich can serve as a vehicle or medium for the active ingredient.

Some examples of pharmaceutically acceptable excipients are found inRemington's Pharmaceutical Sciences and the Handbook of PharmaceuticalExcipients and include diluents, vehicles, carriers, ointment bases,binders, disintegrates, lubricants, glidants, sweetening agents,flavoring agents, gel bases, sustained release matrices, stabilizingagents, preservatives, solvents, suspending agents, buffers,emulsifiers, dyes, propellants, coating agents, and others.

The present pharmaceutical compositions are preferably formulated in aunit dosage form, each dosage typically containing from about 0.5 mg toabout 1000 mg of the compounds of the invention. The term “unit dosageform” refers to a physically discrete unit suitable as a single dosage,each unit containing a predetermined quantity of active ingredient, inassociation with a suitable pharmaceutical excipient, by which one ormore is used throughout the dosing regimen to produce the desiredtherapeutic effect.

In one particular variation, the composition is a pharmaceuticalcomposition adapted for oral administration, such as a liquidformulation, for example, a solution or suspension, adapted for oraladministration or a tablet or a capsule. In still another particularvariation, the pharmaceutical composition is a liquid formulationadapted for parenteral administration.

In another embodiment, the invention provides methods of treatingconditions associated with BTK (Bruton's Tyrosine Kinase), comprising:administering to a patient in need thereof an effective amount of acompound of the invention. In another embodiment, the invention providesa method of inhibiting a BTK: comprising, contacting the enzyme with acompound of the invention. In a further embodiment, the inventionprovides a method of inhibiting BTK: comprising, administering a firstcompound to a subject that is converted in vivo to a compound of theinvention.

“Conditions associated with BTK” include disorders and diseases in whichthe inhibition of BTK provides a therapeutic benefit, such as cancer,allergy/asthma, diseases and conditions of the immune system,inflammation, disease and conditions of the central nervous system(CNS), cardiovascular disease, viral infections, dermatological disease,and diseases and conditions related to uncontrolled angiogenesis, andthe like. Where general terms are used herein to describe conditionsassociated with BTK it is understood that the more specificallydescribed conditions mentioned in the various diagnostic manuals andother materials are included within the scope of this invention.

For example, it is understood that the treatment of cancer includestreatment of all neoplasia, regardless of their histopathologicalappearance. Particularly, the cancers that can be treated include, butare not limited to, cancer of blood, including myelofibrosis, leukemia(including acute myelogenous leukemia, chronic myelogenous leukemia,acute lymphocytic leukemia, chronic lymphocytic leukemia), cancer of theskin, including melanoma, basal cell carcinoma, and squamous cellcarcinoma, bone, liver, lung (including small-cell lung tumor, nonsmall-cell lung cancer and bronchioalveolar cancer), brain, breast,prostate, larynx, gall bladder, pancreas, rectum, bile duct,parathyroid, thyroid, adrenal, neural tissue, bladder, spleen, head andneck, included the jaw, mouth, and nose, colon, stomach, testes,esophagus, uterus, cervix and vulva, colorectal, bronchi, bile duct,bladder, kidney, ovary, pancreas, multiple myeloma, lymphomas, basalcell carcinoma, squamous cell carcinoma of both ulcerating and papillarytype, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma,giant cell tumor, islet cell tumor, acute and chronic lymphocytic andgranulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullarycarcinoma, pheochromocytoma, mucosal neuronms, intestinalganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitustumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor,cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma,myelodysplastic syndrome, mycosis fungicide, rhabdomyosarcoma,astrocytoma, non-Hodgkin's lymphoma, Kaposi's sarcoma, osteogenic andother sarcoma, malignant hypercalcemia, polycythermia vera,adenocarcinoma, glioblastoma multiforma, glioma, lymphomas, epidermoidcarcinomas, and other carcinomas and sarcomas.

Benign tumors may also be treated by the compounds of the presentinvention and include, but are not limited to, hemangiomas,hepatocellular adenoma, cavernous haemangioma, focal nodularhyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bileduct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas,myxomas, nodular regenerative hyperplasia, trachomas, pyogenicgranulomas, and the like, and hamartoma conditions such as Peutz-JeghersSyndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba Syndrome(BRRS), Proteus syndrome, Lhermitte-Duclos disease and TuberousSclerosis (TSC).

The compounds of the present invention may also be used to treatabnormal cell proliferation due to insults to body tissue duringsurgery. These insults may arise as a result of a variety of surgicalprocedures such as joint surgery, bowel surgery, and cheloid scarring.Diseases that produce fibrotic tissue include emphysema. Repetitivemotion disorders that may be treated using the present invention includecarpal tunnel syndrome.

The compounds of the invention may also be useful in the prevention ofrestenosis that is the control of undesired proliferation of normalcells in the vasculature in response to the introduction of stents inthe treatment of vasculature disease.

Proliferative responses associated with organ transplantation that maybe treated using BTK inhibitors of the invention include proliferativeresponses contributing to potential organ rejections or associatedcomplications. Specifically, these proliferative responses may occurduring transplantation of the heart, lung, liver, kidney, and other bodyorgans or organ systems.

The compounds of the invention may also be useful the treatment ofabnormal angiogenesis including the abnormal angiogenesis accompanyingrheumatoid arthritis, ischemic-reperfusion related brain edema andinjury, cortical ischemia, ovarian hyperplasia and hypervascularity,(polycystic ovary syndrome), endometriosis, psoriasis, diabeticretinopaphy, and other ocular angiogenic diseases such as retinopathy ofprematurity (retrolental fibroplastic), macular degeneration, cornealgraft rejection, neuroscular glaucoma, Oster Webber syndrome,retinal/choroidal neuvascularization and corneal neovascularization,Best's disease, myopia, optic pits, Stargart's diseases, Pagets disease,vein occlusion, artery occlusion, sickle cell anemia, sarcoid, syphilis,pseudoxanthoma elasticum carotid abstructive diseases, chronicuveitis/vitritis, mycobacterial infections, Lyme's disease, systemiclupus erythematosis, retinopathy of prematurity, Eales disease, diabeticretinopathy, macular degeneration, Bechets diseases, infections causinga retinitis or chroiditis, presumed ocular histoplasmosis, parsplanitis, chronic retinal detachment, hyperviscosity syndromes,toxoplasmosis, trauma and post-laser complications, diseases associatedwith rubesis (neovascularization of the angle), diseases caused by theabnormal proliferation of fibrovascular or fibrous tissue including allforms of proliferative vitreoretinopathy, atopic keratitis, superiorlimbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea,phylectenulosis, diabetic retinopathy, retinopathy of prematurity,corneal graft rejection, Mooren's ulcer, Terrien's marginaldegeneration, marginal keratolysis, polyarteritis, Wegener sarcoidosis,scleritis, periphigoid radial keratotomy, neovascular glaucoma andretrolental fibroplasia, syphilis, Mycobacteria infections, lipiddegeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpessimplex infections, Herpes zoster infections, protozoan infections, andKaposi sarcoma, Alzheimer's disease, Parkinson's disease amyotrophiclateral sclerosis (ALS), epilepsy, seizures, Huntington's disease,polyglutamine diseases, traumatic brain injury, ischemic andhemorrhaging stroke, cerebral ischemias or neurodegenerative disease,including apoptosis-driven neurodegenerative disease, caused bytraumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity.

For example, it is understood that treatments of inflammation include,but are not limited to, acute pancreatitis, chronic pancreatitis,asthma, allergies, chronic obstructive pulmonary disease, adultrespiratory distress syndrome and chronic inflammatory diseasesassociated with uncontrolled angiogenesis, inflammatory bowel diseasessuch as Crohn's disease and ulcerative colitis, psoriasis, sarcoidois,and rheumatoid arthritis, sarcoidosis, and multisystem granulomatousdisorder.

For example, it is understood that treatment of autoimmune includes, butis not limited to, glomerulonephritis, rheumatoid arthritis, systemiclupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease,autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. hostdisease, multiple sclerosis, or Sjoegren's syndrome.

The compounds of the present invention are also useful for treatingobesity, diabetes, insulin resistance, metabolic syndrome, andhyperlipidemia.

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with the compounds according to the presentinvention. Combination therapies that comprise one or more compounds ofthe present invention with one or more other therapeutic agents can beused, for example, to: (1) enhance the therapeutic effect(s) of the oneor more compounds of the present invention and/or the one or more othertherapeutic agents; (2) reduce the side effects exhibited by the one ormore compounds of the present invention and/or the one or more othertherapeutic agents; and/or (3) reduce the effective dose of the one ormore compounds of the present invention and/or the one or more othertherapeutic agents. It is noted that combination therapy is intended tocover when agents are administered before or after each other(sequential therapy) as well as when the agents are administered at thesame time.

Examples of such therapeutic agents that may be used in combination withthe present compounds include, but are not limited to, anti-cellproliferation agents, anticancer agents, alkylating agents, antibioticagents, antimetabolic agents, hormonal agents, plant-derived agents, andbiologic agents.

Examples of such therapeutic agents that may be used in combination withthe compounds disclosed herein include, but are not limited to,anti-cell proliferation agents, anticancer agents, alkylating agents,antibiotic agents, antimetabolic agents, hormonal agents, plant-derivedagents, and biologic agents.

Anti-cell proliferation agents useful in combination with the compoundsof the present invention include, but are not limited to, retinoid acidand derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN™ protein,ENDOSTATIN™ protein, suramin, squalamine, tissue inhibitor ofmetalloproteinase-I, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel, platelet factor 4, protaminesulphate (clupeine), sulphated chitin derivatives (prepared from queencrab shells), sulphated polysaccharide peptidoglycan complex (sp-pg),staurosporine, modulators of matrix metabolism, including for example,proline analogs ((1-azetidine-2-carboxylic acid (LACA),cishydroxyproline, d,1-3,4-dehydroproline, thiaproline,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta.-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpha-2-antiplasmin, bisantrene, lobenzarit disodium,n-(2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide, angostatic steroid, cargboxynaminolmidazole,metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents that may be used include antibodies, preferably monoclonalantibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5,VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2.

Inhibitors of mTOR, PI3K, MEK, MAPK, JAK, or ERK kinases are useful incombination with the compounds of the present invention. Specifically,(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dioneuseful in combination with the compounds of the present invention.Inhibitors of Hedgehog kinase are useful in combination with thecompounds of the present invention. Proteasome inhibitors, in particularbortezomib is useful in combination with the compounds of the presentinvention.

NAE inhibitors, VPS34 inhibitors, Aurora kinase, including Aurora Ainhibitors, and EGFR inhibitors (both antibodies and kinase inhibitors)are useful in combination with the compounds of the present invention.

Alkylating agents useful in combination with the compunds disclosedherein include, but are not limited to, bischloroethylamines (nitrogenmustards, e.g. chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa),alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine,lomustine, streptozocin), nonclassic alkylating agents (altretamine,dacarbazine, and procarbazine), platinum compounds (carboplastin andcisplatin). Combination therapy including a BTK inhibitor and analkylating agent is expected to have therapeutic synergistic effects inthe treatment of cancer and reduce sides affects associated with thesechemotherapeutic agents.

Examples of antibiotic agents useful in combination with the compoundsdisclosed herein include, but are not limited to, anthracyclines (e.g.doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione),mitomycin C, bleomycin, dactinomycin, plicatomycin. These antibioticagents interfere with cell growth by targeting different cellularcomponents.

Antimetabolic agents useful in combination with the compounds disclosedherein include, but are not limited to, fluorouracil (5-FU), floxuridine(5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, and gemcitabine. Combination therapyincluding a compound disclosed herein and an antimetabolic agent isexpected to have therapeutic synergistic effects on cancer and reducesides affects associated with these chemotherapeutic agents.

Hormonal agents useful in combination with the compounds disclosedherein include synthetic estrogens (e.g. diethylstibestrol),antiestrogens (e.g. tamoxifen, toremifene, fluoxymesterol andraloxifene), antiandrogens (bicalutamide, nilutamide, and flutamide),aromatase inhibitors (e.g., aminoglutethimide, anastrozole andtetrazole), ketoconazole, goserelin acetate, leuprolide, megestrolacetate and mifepristone.

Combination therapy including a compound disclosed herein and a hormonalagent is expected to have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Plant-derived agents useful in combination with the compounds disclosedherein include, but are not limited to, vinca alkaloids (e.g.,vincristine, vinblastine, vindesine, vinzolidine and vinorelbine),podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)),taxanes (e.g., paclitaxel and docetaxel), nab-paclitaxel. Theseplant-derived agents generally act as antimitotic agents that bind totubulin and inhibit mitosis. Podophyllotoxins such as etoposide arebelieved to interfere with DNA synthesis by interacting withtopoisomerase II, leading to DNA strand scission. Combination therapyincluding a compound disclosed herein and a plant-derived agent isexpected to have therapeutic synergistic effects on cancer and reducesides affects associated with these chemotherapeutic agents

As used herein, the term “effective amount” refers to the amount ofcompound of the invention which treats, upon single or multiple doseadministration, a patient suffering from the mentioned condition. Aneffective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount, the dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of patient; its size, age, and general health; thespecific condition, disorder, or disease involved; the degree of orinvolvement or the severity of the condition, disorder, or disease, theresponse of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances. An effective amount of the present use invention,including a compound of the invention, is expected to vary from about0.1 milligram per kilogram of body weight per day (mg/kg/day) to about40 mg/kg/day. Specific amounts can be determined by the skilled person.

In a particular embodiment the present invention provides a method fortreating cancer, comprising: administering to a patient in need thereofan effective amount of a compound of invention.

The invention also provides an article of manufacture: comprising atleast one compound of the invention and a label. The label may includeinformation about the manufacturer, doses, conditions to be treated, andthe use of the compound or pharmaceutical composition.

In another embodiment the invention provides a kit: comprising, at leastone compound of the invention, a label, and apparatus foradministration. The apparatus may include mixing vials, liquids forforming solutions or suspensions, tubing, syringes, and the like.

EXEMPLARY COMPOUNDS

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Exemplary Further Forms of Compounds

Compounds described herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Separation ofsteroisomers may be performed by chromatography. Alternatively,individual stereoisomers may be obtained by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers.

While resolution of enantiomers can be carried out using covalentdiastereomeric derivatives of the compounds described herein,dissociable complexes are also possible (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chiralchromatography, or by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981, herein incorporated by reference in its entirety.Stereoisomers may also be obtained by stereoselective synthesis.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the formulas described herein.

In some cases, cyclic compounds described herein may be in equilibriumwith open chain forms. Closed cyclic forms as well as the correspondingopen chain forms, which are in equilibrium with the closed cyclic forms,are considered part of the present disclosure.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

To produce a prodrug, a pharmaceutically active compound is modifiedsuch that the active compound will be regenerated upon in vivoadministration. The prodrug can be designed to alter the metabolicstability or the transport characteristics of a drug, to mask sideeffects or toxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound. See, e.g., Nogrady (1985) Medicinal ChemistryA Biochemical Approach, Oxford University Press, New York, pages388-392; Silverman (1992), The Organic Chemistry of Drug Design and DrugAction, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al.,(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. (1985),each of which is incorporated by reference herein in its entirety.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a derivative as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporated byreference herein in their entirety.

Sites on the aromatic ring portion of compounds described herein can besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, such as, byway of example only, halogens can reduce, minimize or eliminate thismetabolic pathway.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by other means, including, but not limited to, the useof chromophores or fluorescent moieties, bioluminescent labels, orchemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ₂H, ₃H, ₁₃C, ₁₄C, ₁₅N, ₁₈O, ₁₇O, ₃₅S, ₁₈F, ₃₆Cl, respectively.Certain isotopically-labeled compounds described herein, for examplethose into which radioactive isotopes such as ₃H and ₁₄C areincorporated, are useful in drug and/or substrate tissue distributionassays. Further, substitution with isotopes such as deuterium, i.e., ₂H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,metaphosphoric acid, and the like; or with an organic acid, such as, forexample, acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,trifluoroacetic acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; (2) salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium),an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion;or coordinates with an organic base. Acceptable organic bases includeethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine,and salts with amino acids such as arginine, lysine, and the like.Acceptable inorganic bases used to form salts with compounds thatinclude an acidic proton, include, but are not limited to, aluminumhydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate,sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Compounds described herein may be in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Exemplary Preparation of Compounds

The synthesis of compounds described herein may be accomplished usingmeans described in the chemical literature, using the methods describedherein, or by a combination thereof.

Compounds described herein may be synthesized using standard synthetictechniques known to those of skill in the art or using methods known inthe art in combination with methods described herein. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary according to those of skill in the art.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.), orSigma Chemical Co. (St. Louis, Mo.). The compounds described herein, andother related compounds having different substituents can be synthesizedusing techniques and materials described herein as well as those thatare known to those of skill in the art, such as described, for example,in March, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley 1992); Careyand Sundberg, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., Vols. A and B(Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS 3.sup.rd Ed., (Wiley 1999), each of which is incorporated byreference herein in its entirety.

General methods for the preparation of compound as disclosed herein maybe derived from known reactions in the field, and the reactions may bemodified by the use of appropriate reagents and conditions, as would berecognized by the skilled person, for the introduction of the variousmoieties found in the formulae as provided herein. As a guide thefollowing synthetic methods may be utilized.

In various embodiments, provided herein are compounds of the Formula I:

or a pharmaceutically acceptable salt, solvate, analog, prodrug, isomeror tautomer thereof, wherein X₁, X₂, R₃, R₄, Y₁, Y₂, Y₃, and G are asdefined herein.

These embodiments of the invention can be synthesized using methodsknown in the art. A specific synthetic method for preparing compounds ofFormula I is shown in Scheme A below:

In Scheme A, Step 1 depict the condensation reactions of a compound offormula (a) with an ammonia source such as NH₄OAc in an appropriatesolvent such as MeOH under heating conditions, to give a compound offormula (b).

Step 2 depicts the acylation reaction of an appropriate compound offormula (b) to give a compound of formula (c). Such acylation reactionsare well understood and appreciated.

Step 3 depicts the cyclization reaction of a compound of formula (c) togive a compound of formula (d) in an appropriate solvent under variousbasic conditions. Such cyclization coupling reactions are wellunderstood and appreciated.

Step 4 depicts the chlorination of a compound of formula (d) to give acompound of formula (e). Such chlorination reactions of carbonyls to thecorresponding vinylchlorides well understood and appreciated.

Step 5 depicts the condensation reactions of a compound of formula (e)with an appropriate hydrazine (NH₂—NH₂—R₃) to give a compound of formula(f). Such condensation reactions to form aminopyrazoles are wellunderstood and appreciated.

Step 6 depicts the reduction reaction of a compound of formula (f) togive a compound of formula (g). Such reductions of a —NO₂ group to thecorresponding —NH₂ group can be carried out under a variety ofconditions.

Step 7 depicts the acylation reactions of a compound of formula (g) togive a compound of Formula I. Such acylation reactions can be carriedout under a variety of conditions.

It will be recognized by one of ordinary skill in the art that the stepsin Scheme A to I may be varied to provide compounds of Formula I, II,III, IV, V, VI, VII, VIII. In particular, the order of the stepsrequired to produce the compounds of Formula I, II, III, IV, V, VI, VII,VIII is dependent upon the particular compound being synthesized, thestarting compound, and the relative lability of the substitutedmoieties.

It is also understood that some compounds of Formula I, II, III, IV, V,VI, VII, VIII may be elaborated to other compounds of Formula I, II,III, IV, V, VI, VII, VIII, in additional steps not shown. Compounds ofFormula I, II, III, IV, V, VI, VII, VIII may be elaborated in a varietyof other ways. Such reactions include hydrolysis, oxidation, reduction,alkylation, amidations, sulfonations, alkynations, alkyenations, and thelike. Also, in an optional step (not shown) the compounds of Formula I,II, III, IV, V, VI, VII, VIII can be converted to pharmaceuticallyacceptable salts by methods well known and appreciated in the art.

Exemplary Compounds

Specific non-limiting examples of compounds falling within Formula IIIare:

Specific non-limiting examples of compounds falling within Formula IVare:

Specific non-limiting examples of compounds falling within Formula Vare:

Specific non-limiting examples of compounds falling within Formula VIare:

Specific non-limiting examples of compounds falling within Formula VIIare:

In some specific embodiments, provided herein are compounds of FormulaVIII:

Having now generally described the invention, the same will be morereadily understood through reference to the following examples which areprovided by way of illustration, and are not intended to be limiting ofthe present invention, unless specified.

EXAMPLES Preparation 1A methyl 2-(2-hydroxyphenyl)acetate

To a solution of 2-(2-hydroxyphenyl)acetic acid (400 g, 2.63 mmol) inMeOH (3.0 L) was bubbled with HCl (g) at room temperature for 2 hours.The resulting mixture was concentrated, dried under vacuo to givecompound 1A (415 g, yield 95%) as yellow oil, and the oil was solidifiedafter standing overnight.

¹H NMR (CDCl₃, 400 MHz): δ 7.20-7.16 (m, 1H), 7.11-7.09 (m, 1H),6.93-6.86 (m, 2H), 4.48 (br s, 1H), 3.74 (s, 2H), 3.69 (s, 3H).

Preparation 1B methyl 2-(2-hydroxy-3-nitrophenyl)acetate

To a suspension of compound 1A (415 g, 2.50 mol) in petroleum ether (PE)(3.0 L) was added dropwise HNO₃ (68% wt)/Ac₂O (250 mL/2.5 L) at 0° C.during 3 hours and keep the temperature between 10-30° C. The reactionmixture was poured into crashed ice, extracted with EtOAc. The organiclayer was washed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The residue was triturated with petroleum ether/EtOAc(5:1) and purified by column chromatography on silica gel eluting withPE/EtOAc (15:1) to give the compound 1B (240 g, yield 46%) as a yellowsolid. ¹H NMR (CDCl₃, 400 MHz): δ 10.93 (s, 1H), 8.06 (dd, J=4.8, 2.0Hz, 1H), 7.52 (dd, J=7.2, 1.2 Hz, 1H), 6.97 (dd, J=8.0, 7.6 Hz, 1H),3.76 (s, 2H), 3.73 (s, 3H).

Preparation 1C methyl 2-[2-(2-methoxy-2-oxoethyl)-6-nitrophenoxy]acetate

A mixture of compound 1B (240 g, 1.14 mol), methyl 2-bromoacetate (210g, 1.37 mol) and K₂CO₃ (236 g, 1.71 mol) in CH₃CN was refluxedovernight. After concentration, the residue was diluted with water,extracted with EtOAc. The organic layer was washed with water and brine,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby column chromatography on silica gel eluting with PE/EtOAc (10:1) togive compound 1C (170 g, yield 53%) as yellow oil. ¹H NMR (CDCl₃, 300MHz): δ 7.86-7.84 (m, 1H), 7.56-7.53 (m, 1H), 7.28-7.23 (m, 1H), 4.67(s, 2H), 3.91 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H).

Preparation 1D methyl 3-hydroxy-8-nitro-2H-chromene-4-carboxylate

To a solution of compound 1C (30.0 g, 0.106 mol) in anhydrous THF (300mL) was added t-BuOK (17.8 g, 0.159 ml) in portions at room temperature.After stirred at room temperature for 2 hours, the reaction mixture wasconcentrated. The residue was dissolved in water (500 mL), washed withEtOAc (250 mL*3, abandoned), the aqueous layer was acidified with 6N HClto pH<3, and filtrated. The collected solid was dried under high vacuoto give compound 1D (14.0 g, yield 52%) as a yellow solid. ¹H NMR(CDCl₃, 400 MHz): δ 12.99 (s, 1H), 7.96 (dd, J=10.8, 2.0 Hz, 1H), 7.60(dd, J=10.8, 2.0 Hz, 1H), 7.04 (t, J=10.8 Hz, 1H), 4.79 (s. 2H), 3.98(s, 3H).

Preparation 1E methyl 3-amino-8-nitro-2H-chromene-4-carboxylate

A solution of compound 1D (14.0 g, 55.8 mmol) and NH₄OAc (21.5 g, 0.279mol) in MeOH (200 mL) was refluxed overnight. After cooled to roomtemperature, the reaction mixture was diluted with water (200 mL), andconcentrated to remove MeOH. The resulting mixture was filtrated, thefilter cake was washed with water, dried under vacuo to give compound 1E(12.8 g, yield 92%) as a yellow solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 8.03(dd, J=8.1, 0.6 Hz, 1H), 7.47 (dd, J=8.1, 1.2 Hz, 1H), 7.06 (t, J=8.1Hz, 1H), 4.72 (s, 2H), 3.75 (s, 3H).

Preparation Example 1F methyl3-(2-cyanoacetamido)-8-nitro-2H-chromene-4-carboxylate

To a mixture of compound 1E (33.0 g, 0.132 mol) and 2-cyanoacetic acid(23.0 g, 0.264) in anhydrous toluene (350 mL) was added POCl₃ (10 mL)and refluxed for 2 hours. After cooled to room temperature, the reactionmixture was concentrated and added crashed ice. The resulting mixturewas basified with saturated NaHCO₃, filtrated. The filter cake wastriturated with less EtOAc, filtrated and the collected solid was driedunder vacuo to afford compound 1F (24.8 g, yield 59%) as a yellow solid.¹H NMR (DMSO-d₆, 300 MHz): δ 10.61 (s, 1H), 7.80-7.77 (m, 2H), 7.16 (t,J=8.1 Hz, 1H), 5.08 (s, 2H), 4.02 (s, 2H), 3.82 (s, 3H).

Preparation Example 1G7-nitro-1,3-dioxo-1H,2H,3H,4H,5H-chromeno[3,4-b]pyridine-2-carbonitrile

To a solution of compound 1F (25.0 g, 78.9 mmol) in anhydrous THF (200mL) was added dropwise LiHMDS (197 mL, 0.197 mol) at −78° C. and stirredfor 5 min. The reaction mixture was quenched with saturated NH₄Cl, andfiltered. The filter cake was washed with water, dried under vacuo togive compound 1G (19.0 g, yield 84%) as a yellow solid. ¹H NMR (DMSO-d₆,300 MHz): δ 11.47 (s, 1H), 8.70 (dd, J=7.8, 1.2 Hz, 1H), 7.67 (dd,J=8.4, 1.5 Hz, 1H), 7.15 (t, J=8.1 Hz, 1H), 5.00 (s, 2H).

Preparation Example 1H1-chloro-7-nitro-3-oxo-3H,4H,5H-chromeno[3,4-b]pyridine-2-carbonitrile

To a solution of compound 1G (19.5 g, 68.4 mmol) in POCl₃ (120 mL) wasadded dropwise TEA (17.3 g, 0.171 mol) at room temperature and heated to75° C. for 30 min. After cooled to room temperature, the reactionmixture was concentrated. The residue was basified with aq NaHCO₃, theresulting mixture was filtrated, the filter cake was washed with water,dried under vacuo to give compound 1H (12.4 g, yield 60%) as a yellowsolid. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.26 (d, J=8.8 Hz, 1H), 7.67 (d,J=7.2, Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 4.82 (s, 2H).

Preparation Example 1I14-amino-15-(5-methoxy-2-methylphenyl)-6-nitro-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-12-one

To a mixture of compound 1H (1.21 g, 4.0 mmol),(5-methoxy-2-methylphenyl)hydrazine-HCl (prepared according to procedurefound in Patent EP1719771 A1, 2006) (0.80 g, 4.24 mmol) and K₂CO₃ (1.1g, 8.0 mmol) in EtOH (50 mL) was refluxed overnight. After cooled toroom temperature, the reaction mixture was diluted with water,filtrated, the filter cake was washed with water, dried under vacuo toafford crude compound 1I (1.1 g) as a yellow solid, which was used inthe next step without further purification.

Preparation Example 1J6,14-diamino-15-(5-methoxy-2-methylphenyl)-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-12-one

To a suspension of compound 1I (1.10 g, 2.63 mmol) and SnCl₂.2H₂O (0.644g, 5.72 mmol) in EtOH was refluxed for 1 hour. After cooled to roomtemperature, the reaction mixture was basified with aq Na₂CO₃ solution,and the resulting mixture was filtered. The collected solid was washedwith water and purified with prep-HPLC to give compound 1J (100 mg,yield 10%) as a white solid. ¹H NMR (DMSO-d6, 400 MHz): δ 10.59 (s, 1H),7.52 (d, J=7.2 Hz, 1H), 7.34 (d, J=11.6 Hz, 1H), 7.04 (d, J=11.2 Hz,1H), 6.94 (d, J=3.6 Hz, 1H), 6.65 (d, J=10.0 Hz, 1H), 6.50 (t, J=10.8Hz, 1H), 6.19 (s, 2H), 4.92 (s, 2H), 4.68 (s, 2H), 3.79 (s, 3H), 2.01(s, 3H).

Preparation Example 1K6,14-diamino-15-(5-hydroxy-2-methylphenyl)-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-12-one

A solution of compound 1J (100 mg, 0.26 mmol) and methionine (20 mg,0.133 mol) in methanesulfonic acid (1 mL) was stirred at 100° C. for 2hours. After cooled to room temperature, the reaction mixture wasbasified with aq NaOH (40%) to pH=3. The resulting mixture was filteredand the filter cake was dissolved in MeOH and concentrated. The residuewas purified by prep-HPLC to give compound 1K (86 mg, yield 88%) as atan solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 10.58 (s, 1H), 9.63 (s, 1H),7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 6.86 (dd, J=8.4,2.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.68 (t, J=4.5 Hz, 1H), 6.50 (dd,J=8.1, 1.5 Hz, 1H), 6.14 (s, 2H), 4.91 (s, 2H), 4.67 (s, 2H), 2.08 (s,3H).

Preparation Example 1N-[14-amino-15-(5-hydroxy-2-methylphenyl)-12-oxo-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-6-yl]prop-2-enamide

To a solution of compound 1J (150 mg, 0.40 mmol) and TEA (81 mg, 0.80mmol) in anhydrous THF (2 mL) was added dropwise prop-2-enoyl chloride(44 mg, 0.44 mmol) in THF (1 mL) at 0° C. and stirred for 1 hour. Theresulting mixture was quenched with MeOH (2 mL), concentrated andpurified by prep-HPLC to give compound 1 (11 mg, yield 6%) as a whitesolid. ¹H NMR (DMSO-d₆, 300 MHz): δ 10.66 (s, 1H), 9.66 (s, 1H), 9.46(s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.83-7.81 (m, 1H), 7.23 (d, J=8.1 Hz,1H), 6.97-6.86 (m, 2H), 6.75 (d, J=1.8 Hz, 1H), 6.69-6.64 (m, 1H),6.27-6.20 (m, 3H), 5.73 (dd, J=9.9, 1.2 Hz, 1H), 5.04 (s, 2H), 1.98 (s,3H). [M+H] found 430).

Preparation Example 2(2E)-N-[14-amino-15-(5-hydroxy-2-methylphenyl)-12-oxo-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-6-yl]-4-(dimethylamino)but-2-enamide

To a solution of (2E)-4(dimethylamino)but-2-enoic acid (250 mg, 1.2mmol) in DCM was added one drop DMF and then added dropwise oxaylchloride (150 mg, 1.15 mmol) at 0° C., and stirred at rt for 30 min, andconcentrated. The residue was dissolved in THF (1 mL), added dropwise toa solution of compound 1J (120 mg, 0.32 mmol) in THF (3 mL) at 0° C.,and stirred for 2 hours. The resulting mixture was quenched with MeOH,concentrated, and the residue was purified by prep-HPLC to give 2 (28mg, yield 18%) as white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 10.66 (s,1H), 9.66 (s, 1H), 9.36 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.83-7.80 (m,1H), 7.23 (d, J=8.4 Hz, 1H), 6.95-6.86 (m, 2H), 6.76-6.67 (m, 2H), 6.50(d, J=15.6 Hz, 1H), 6.20 (s, 2H), 5.02 (s, 2H), 3.04 (d, J=5.7 Hz, 1H),2.18 (s, 6H), 1.98 (s, 3H). [M+H] found 487.

Preparation Example 3A14-amino-6-nitro-15-(4-phenoxyphenyl)-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-12-one

A mixture of compound 1H (1.00 g, 3.29 mmol),(4-phenoxyphenyl)hydrazine-HCl (0.86 g, 3.6 mmol) and K₂CO₃ (0.91 g, 6.6mmol) in EtOH (50 mL) was refluxed overnight. After cooled to roomtemperature, the reaction mixture was diluted with water, filtrated, thefilter cake was washed with water, dried under vacuo to afford crudecompound 3A (280 mg, yield 18%) as a yellow solid, which was used in thenext step without further purification. [M+H] found 468.

Preparation Example 3B6,14-diamino-15-(4-phenoxyphenyl)-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-12-one

A suspension of compound 3A (250 mg, 0.540 mmol) and SnCl₂.2H₂O (483 mg,2.14 mmol) in EtOH and NMP was refluxed for 2 hours. After cooled toroom temperature, the reaction mixture was basified with aq Na₂CO₃solution, and the resulting mixture was filtered. The collected solidwas washed with water and purified with prep-HPLC to give compound 3B(90 mg, yield 38%) as a white solid. [M+H] found 438.

Preparation Example 3(2E)-N-[14-amino-12-oxo-15-(4-phenoxyphenyl)-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-6-yl]-4-(dimethylamino)but-2-enamide

To a solution of (2E)-4(dimethylamino)but-2-enoic acid (124 mg, 0.96mmol) in DCM was added one drop DMF and then added dropwise oxaylchloride (72.4 mg, 0.57 mmol) at 0° C., and stirred at 0° C. for 30 minand concentrated. The residue was dissolved in THF (0.5 mL), addeddropwise to a solution of compound 3B (130 mg, 0.300 mmol) in THF (1.5mL) at 0° C., and stirred for 2 hours. The resulting mixture wasquenched with MeOH, concentrated, and the residue was purified byprep-HPLC to give 3 (33.8 mg, yield 21%) as a white solid. ¹H NMR(DMSO-d₆, 300 MHz): δ 10.74-10.73 (br, 1H), 9.39 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.45 (t, J=8.1Hz, 2H), 7.22-7.17 (m, 3H), 7.11 (d, J=7.8 Hz, 2H), 6.96 (t, J=7.8 Hz,1H), 6.74-6.66 (m, 1H), 6.52-6.49 (m, 3H), 5.02 (s, 2H), 3.06-3.04 (m,2H), 2.18 (s, 6H). [M+H] found 549.

Preparation Example 4N-[14-amino-15-(2-fluorophenyl)-12-oxo-8-oxa-11,15,16-triazatetracyclo[8.7.0.0^(2,7).0^(13,17)]heptadeca-1(10),2(7),3,5,13,16-hexaen-6-yl]prop-2-enamide

Example 4 was prepared following a similar chemistry sequence as inExample 1, using (2-fluorophenyl)hydrazine in the aminopyrazoleformation step. [M+H] found 418.

Example 5

BTK activity was determined using Invitrogen's SelectScreen® BiochemicalKinase Profiling Service using the Z′-LYTE Screening Protocol and AssayConditions (ATP concentration at Km).

The exemplified compounds inhibited human BTK in the assay of Example 5with an IC₅₀ of: +++ less than about 10 nM, ++ between 10 and 100 nM,and + greater than 100 nM as shown in Table 1.

TABLE 1 Example No. BTK IC₅₀ (nM) 1 +++ 2 +++ 3 +++ 4 ++

What is claimed is:
 1. A method of treating a subject with a conditionassociated with Bruton's Tyrosine Kinase (“BTK”) comprisingadministering an effective amount of a compound of Formula I:

or pharmaceutically acceptable salt, solvate, or tautomer thereofwherein: X₁ and X₂ are independently selected from O, NR₁, or CR₁R₂;wherein, R₁ and R₂ are independently selected from H, halogen,substituted or unsubstituted C₁-C₈ alkyl and heteroalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl and heterocycloalkyl; and R₁ and R₂ canbe joined to form a ring; Y₁, Y₂, and Y₃ are independently selected fromN, CH, or CR₁; R₃ is Ar or

 wherein L_(a) is CH₂, O, NH, or S; Ar is a substituted or unsubstitutedaryl, or a substituted or unsubstituted heteroaryl; R₄ and R₅ areindependently selected from H, substituted or unsubstituted C₁-C₈ alkyl;and G is

 where (a) R₇ and R₈ are H; R₆ is H, substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl,substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, or C₁-C₈ alkylamides; (b) R₆ and R₈ are H; R₇ is H,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstitutedC₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl,C₁-C₈ alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, or C₁-C₈ alkylamides; or (c) R₇ and R₈ taken together forma bond; R₆ is substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈ alkylC₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₈ alkylethers, or C₁-C₈ alkylamides, or; G is

 where R₆ is H, substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈ alkylC₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₈ alkylethers, or C₁-C₈ alkylamides; wherein thecondition associated with Bruton's Tyrosine Kinase (“BTK”) ismyelofibrosis, acute myelogenous leukemia (AML), acute lymphoticleukemia (ALL), or chrinoc lymphocytic leukemia (CLL).
 2. The method ofclaim 1, wherein R₄ is H or methyl.
 3. The method of claim 1, wherein Gis


4. The method of claim 3, wherein R₄ is H or methyl.
 5. The method ofclaim 1 having Formula II:

or pharmaceutically acceptable salt, solvate, or tautomer thereofwherein: X₁ and X₂ are independently selected from O, NR₁, or CR₁R₂;wherein, R₁ and R₂ are independently selected from H, halogen,substituted or unsubstituted C₁-C₈ alkyl and heteroalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl and heterocycloalkyl; and R₁ and R₂ canbe joined to form a ring; L_(a) is CH₂, O, NH, or S; Ar is a substitutedor unsubstituted aryl, or a substituted or unsubstituted heteroaryl; Y₁,Y₂, Y₃, Y₄, Y₅, Y₆, and Y₇ are independently selected from N, CH, orCR₁; R₄ and R₅ are independently selected from H, substituted orunsubstituted C₁-C₈ alkyl; and G is

 where (a) R₇ and R₈ are H; R₆ is H, substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl,substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, or C₁-C₈ alkylamides; (b) R₆ and R₈ are H; R₇ is H,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstitutedC₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl,C₁-C₈ alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, or C₁-C₈ alkylamides; or (c) R₇ and R₈ taken together forma bond; R₆ is substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈ alkylC₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₈ alkylethers, or C₁-C₈ alkylamides; or G is

 where R₆ is H, substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈ alkylC₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₈ alkylethers, or C₁-C₈ alkylamides.
 6. The method ofclaim 5, wherein R₄ is H or methyl.
 7. The method of claim 5, wherein Gis


8. The method of claim 7, wherein R₄ is H or methyl.
 9. The method ofclaim 1 having Formula IIA:

or pharmaceutically acceptable salt, solvate, or tautomer thereofwherein: L_(a) is CH₂, O, NH, or S; Ar is a substituted or unsubstitutedaryl, or a substituted or unsubstituted heteroaryl; Y₁, Y₂, Y₃, Y₄, Y₅,Y₆, and Y₇ are independently selected from N, CH, or CR₁; R₄ and R₅ areindependently selected from H, substituted or unsubstituted C₁-C₈ alkyl;and G is

 where (d) R₇ and R₈ are H; R₆ is H, substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈alkylaminoalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl,substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, C₁-C₈ alkylamides; (e) R₆ and R₈ are H; R₇ is H,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstitutedC₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈ alkyl C₃-C₆cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₈ alkylethers, or C₁-C₈ alkylamides; or (f) R₇ and R₈taken together form a bond; R₆ is substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈alkoxyalkylammoalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl,substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, or C₁-C₈ alkylamides; or G is

 where R₆ is H, substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈ alkylC₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl, C₁-C₈ alkylethers, or C₁-C₈ alkylamides.
 10. The method ofclaim 9, wherein R₄ is H or methyl.
 11. The method of claim 9, wherein Gis


12. The method of claim 11, wherein R₄ is H or methyl.
 13. The method ofclaim 1, wherein the compound of claim I is of Formula III, Formula IV,Formula V, Formula VI, or Formula VII:

or pharmaceutically acceptable salt, solvate, or tautomer thereofwherein: Ar is a substituted or unsubstituted aryl, or a substituted orunsubstituted heteroaryl; Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, and Y₇ areindependently selected from N, CH, or CR₁; R₄ and R₅ are independentlyselected from H, substituted or unsubstituted C₁-C₈ alkyl; and G is

 where (a) R₇ and R₈ are H; R₆ is H, substituted or unsubstituted C₁-C₄alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl,substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, C₁-C₈ alkylamides, or C₁-C₄ alkyl; (b) R₆ and R₈ are H; R₇is H, substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted C₁-C₄ heteroalkyl, C₁-C₈ alkylaminoalkyl, C₁-C₈hydroxyalkylaminoalkyl, C₁-C₈ alkoxyalkylaminoalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₈ alkylC₃-C₆ cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted C₂-C₈ heterocycloalkyl, substituted or unsubstitutedheteroaryl C₁-C₈ alkylethers, C₁-C₈ alkylamides, or C₁-C₄ alkyl; or (c)R₇ and R₈ taken together form a bond; R₆ is substituted or unsubstitutedC₁-C₄ alkyl, substituted or unsubstituted C₁-C₄ heteroalkyl, C₁-C₈alkylaminoalkyl, C₁-C₈ hydroxyalkylaminoalkyl, C₁-C₈alkoxyalkylaminoalkyl, substituted or unsubstituted C3-C6 cycloalkyl,substituted or unsubstituted C₁-C₈ alkyl C₃-C₆ cycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, C₁-C₈alkylethers, or C₁-C₈ alkylamides.
 14. The method of claim 13, whereinR₄ is H or methyl.
 15. The method of claim 13, wherein G is


16. The method of claim 15, wherein R₄ is H or methyl.
 17. The method ofclaim 1, wherein the compound of Formula I is: